Nonstimulant ADHD Medicines

Nonstimulant medicines for attention deficit hyperactivity disorder (atomoxetine, guanfacine extended release, clonidine extended release, viloxazine) are used when stimulants are ineffective, not tolerated, contraindicated, or risky because of misuse, tics or anxiety. They act over weeks, not hours.

Mechanism. Atomoxetine and viloxazine inhibit the noradrenaline transporter. Guanfacine and clonidine are alpha-2 agonists that strengthen prefrontal signalling.

Pharmacokinetics. Atomoxetine is metabolised by CYP2D6, with a half-life of 5 hours in extensive metabolisers and 21 hours in poor metabolisers. Guanfacine is metabolised by CYP3A4. Viloxazine inhibits CYP1A2 strongly.

Differences. Atomoxetine suits anxiety and substance misuse, but takes 4 to 6 weeks. Guanfacine and clonidine suit tics, aggression, sleep problems and hyperarousal, and are taken in the evening if sedating.

• Choose when: a stimulant has failed or is contraindicated, or comorbid tics, anxiety or substance misuse are present.
• Atomoxetine: reduce the starting dose (and the target) when given with strong CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) or in poor metabolisers.
• Guanfacine and clonidine: never stop abruptly (taper by 1 mg every 3 to 7 days) to avoid rebound hypertension. Reduce guanfacine to half the dose with ketoconazole or ritonavir, and double it with enzyme inducers.
• Adjunct: guanfacine or clonidine added to a stimulant.
• Response: judge after 6 to 8 weeks at a target dose.

Special groups. Pregnancy: limited data; avoid where possible. Breastfeeding: limited data; avoid. Children: all are used from 6 years. Older adults: limited data. Kidney impairment: reduce doses of guanfacine in severe impairment. Liver impairment: halve atomoxetine in moderate disease and reduce to 25% in severe disease. Regional: ultrarapid CYP2D6 metabolism is more frequent in some East African populations, which can lower atomoxetine response.

Adverse effects. Atomoxetine: nausea, appetite loss, fatigue, raised heart rate and blood pressure, urinary hesitancy, sexual dysfunction, suicidal thoughts (boxed concern in children and adolescents), and rare liver injury. Guanfacine and clonidine: sedation, hypotension, bradycardia, dry mouth, and rebound hypertension on abrupt stopping.

Contraindications. Atomoxetine with narrow-angle glaucoma, phaeochromocytoma, severe cardiovascular disease, and monoamine oxidase inhibitors. Guanfacine and clonidine with severe bradycardia, heart block and hypotension.

Interactions. CYP2D6 inhibitors (atomoxetine), CYP3A4 inhibitors and inducers (guanfacine), and antihypertensives and sedatives (additive).

Monitoring. Blood pressure and pulse at baseline, after each dose change and every 6 months, weight and height in children, mood and suicidality (atomoxetine), and liver symptoms.

Referral and escalation. Jaundice (stop atomoxetine), syncope, bradycardia, or suicidal thoughts.